Coronavirus
Structural Task Force

Ironic: Using Viruses to fight the Coronavirus

After mRNA vaccines, there is now another novelty: vector vaccines ‒ like the one from AstraZeneca ‒ contain a mostly functioning virus. But how do they work exactly? What are their strengths and weaknesses? And finally, are they safe?

The novel mRNA vaccines against SARS-CoV-2 have caused some controversy, and the concerns are many.

 While the mRNA vaccines enfold the genetic material in a tiny lipid particle this vaccine puts it in a viral shell that functions as a transporter (vector). This type of vaccine is called a viral vector vaccine.

A large number of vaccines of this type are under development and they all are based on various strains of the same common cold virus. The European Medicines Agency (EMA) recommended the Oxford-AstraZeneca vaccine for approval in late January and the United States approved the use of a similar vaccine from Johnson & Johnson in February. Why?

Viruses are transporters for genes

Viruses are not considered living organisms because they have no metabolism of their own. They contain only the genes that cause the host cell to produce new viruses.

In the evolution of viruses, some skills have become exceptionally refined. Viruses can specifically infect host cells, escape the host's immune defenses, and insert their genetic material into that of the host. Once molecular biologists recognized these capabilities scientists could turn viruses into tools that do not cause disease through genetic engineering. As modified tools, they are referred to as viral vectors.

Viruses as tools

To use viruses for research purposes, they are modified. Their natural genes must be changed or deleted. What is left in the end is a transporter that can be used to introduce desired genes into a host. This method is used, for example, to produce transgenic (genetically modified) plants or cell lines. In this process, researchers usually keep some natural functions of the virus, such as invading host cells.

Viruses as vaccines

So, what exactly must be changed to turn a virus into a vaccine?

In order not to cause a disease, the virus must lose its ability to multiply inside the body. Viruses without the ability to reproduce are called replication deficient. In the past, replication was disabled via lengthy cell culture techniques but, since the 2000s, genetic engineering has made it possible to selectively remove or modify genes of a virus to stop it from reproducing. Removing critical genes can completely prevent reproduction of the virus and any return to the pathogenic (disease-causing) variant can be prevented [3].

Gene modification can also be used to introduce structures such as the spike gene of SARS-CoV-2 into a virus that is harmless to humans. This addition turns the virus into a vaccine.

Viruses have been used as tools for a long time. Viral vectors were first described in 1972 [1]. In the early 1990s, a foreign gene was first used for therapy through an attenuated adenovirus [2].

In the last twenty years a number of vaccines based on viruses have been developed. An example of an approved vector vaccine is the Ebola vaccine Erbevo [4]. Because there is no treatment for Ebola to date, the epidemics of 2014-16 and 2018-20 were devastating for Central Africa. Mortality rates were 25-90% [5]. In August 2018, Erbevo was used to vaccinate a large group of peoplefor the first time. It proved to be highly effective [6] and was also licensed in the EU in 2019 [5].

Ironic: Using Viruses to fight the Coronavirus 1
Different forms of vaccines containing viruses. Left: The pathogen has been killed, but the immune system still recognizes the surface and reacts to it. Middle: The virus has had its ability to reproduce weakened, so it no longer causes serious disease. Right: Certain genes of a pathogen have been inserted into a viral vector; this is a harmless and attenuated virus. Source: WHO, https://www.who.int/news-room/feature-stories/detail/the-race-for-a-covid-19-vaccine-explained.

How does the AstraZeneca vaccine work?

This vaccine is called AZD1222 (also called ChAdOx1 nCoV-19) [8]. It is an adenovirus that is similar to a common cold pathogen, but this strain was originally found in chimpanzees. It has been modified to be replication-deficient. AZD1222 was also modified to contain the coronavirus’ surface protein (spike) gene [9]. This chimpanzee virus is used because most people's immune systems are familiar with adenoviruses that infect humans and therefore, their immune systems might respond to those viruses before they can infect cells and produce spike protein. In comparison, the chimpanzee virus is unfamilar to humans and therefore triggers a stronger - and desirable - immune response to the spike protein [10]. Side effects can occur, but they have nothing to do with a disease. Feeling unwell after being vaccinated is triggered by our immune system, which fights against an intruder with all its weapons.

AZD1222 invades some human host cells just like your usual common cold virus. During this process, the vector transports the gene of the spike protein. The spike DNA is utilized by the cell to produce spike protein. Spike is referred to here as an antigen, which is a substance that triggers an immune response. The immune system recognizes it as foreign and starts attacking, antibodies are produced and the few "infected" cells containing AZD1222 genetic material are destroyed. Antibodies bind to the antigen like pieces of a puzzle and hold on to it. The antigen-antibody clumps are then degraded.

What remains from the whole process are memory cells that recognize the spike protein when attacked by the real SARS-CoV-2. Previous training with the vaccine makes the next immune response faster and more efficient. This prevents disease before it can break out.

Development and effect of an adenovirus vector vaccine.

Ironic: Using Viruses to fight the Coronavirus 2
Development and effect of an adenovirus vector vaccine.

How effective and safe is the vaccine?

AZD1222 has already been tested in over 20,000 people in three phases of a clinical trial [11]. Since its approval, data continues to be collected and combined into "real-world" studies. Through these, it is possible to make even more precise statements about possible side effects since millions of people are vaccinated and observed in the "real world".

One example is a British study on efficacy in people over 70 years of age. The result: a single dose is 60-75% effective against a symptomatic Corona infection. The likelihood of hospitalization is also reduced by 80% with the AstraZeneca vaccine, just as with the BioNtech vaccine [12].

The first nationwide study took place in Scotland. It was led by the University of Edinburgh and collected data from 5.4 million vaccinated people. Preliminary data show that AstraZeneca's single-dose vaccine prevented a severe course ‒ requiring hospitalization ‒ in 94% of cases [13].

Through the real-world studies, it is now known that the vector vaccine is more effective with a larger interval between the first and second dose. Therefore, these studies recommend an interval of 12 weeks [14].

In terms of side effects, some data has already been collected on AZC1222 in the UK due to the earlier start of vaccination [15]. Common side effects experienced by one in ten vaccinated people include:

  • Tenderness, pain, warmth, itching, or bruising at the injection site
  • Feeling generally unwell or tired
  • chills or feverish feeling
  • headache
  • nausea
  • joint pain or muscle soreness

These frequent side effects are similar to those of the BioNtech vaccine. However, no serious side effects have been detected in the trials. Fever or flu-like symptoms are less common and are a general sign that the vaccine is activating the immune system and is therefore working. In any case, these symptoms are not comparable to the risks of a severe Covid 19 course.

The EMA is currently looking into cases of blood clotting that occurred shortly after an AstraZeneca vaccination. So far there are no indications that the vaccine is unsafe. The frequency of blood clots in vaccinated people is not higher than it generally is in the population. According to AstraZeneca [15.1] the risk of pulmonary embolism, deep vein thrombosis (DVT) or thrombocytopenia are not higher in vaccinated people compared to the general public. Among 17 million vaccinated people in Europe some will suffer from these diseases, but it is very likely not linked to the vaccine.

What is in the vaccine?

In addition to the modified adenovirus, the vaccine contains several other substances [16].

Most are additives that stabilize the vaccine and make administration easier. These include: Amino acids, stabilizers, alcohol, sugar, salt, binders and water. In addition, the vaccine is free of food allergens (such as soy or lactose) and contains no human or animal ingredients. That sounds incredible for a chimpanzee virus that needs a host to reproduce. How can this be?

All modifications and amplification of the virus took place in a human cell line used in the laboratory for such purposes, so-called HEK293 cells. These cells are, however, not part of the vaccine.

What are the advantages of this type of vaccine?

Viral vector vaccines – just plain RNA/DNA vaccines - can be developed very quickly. The reason: as soon as the genes of the pathogen are known, they can be used for vaccine development. This shortens the time until clinical trials can begin. This makes vector vaccines suitable for sudden epidemic outbreaks [18].

One advantage of the AstraZeneca vaccine is its dosage. Oxford-AstraZeneca initially tested different dosing approaches for their vector vaccine. Vaccinations with two standard doses at intervals of four to twelve weeks and a vaccination with only one dose were compared. Here, a standard dose contains 5x1010 virus particles.

"By using a more effective dosing regimen," said Professor Pollard, the lead scientist at Oxford, "more people could be served by the same amount of vaccine."[20]. For, the ideal regimen was to administer a half dose (2.2x1010 virus particles) followed by a standard dose at least one month apart. The efficiency in this case was 90% [21]. However, this must first be confirmed by more data. So far vaccination is done with two standard doses.

Conclusion

In nature, viruses have perfected the ability to insert their genetic material into hosts. The fascinating abilities of viruses can nowadays be used by scientists. They are therefore used to create genetically modified plants or cells, to treat hereditary diseases and to produce vaccines.

Vector vaccines - such as AstraZeneca's - contain harmless and non-reproducing viruses that contain a part of a disease-causing virus. By artificially "infecting" the patient with the vector vaccine, the immune system is trained to respond to the pathogen and reacts more quickly and effectively in the event of a real infection.

[1] Jackson D.A., Symons R.H., Berg P. Biochemical method for inserting new genetic information into DNA of Simian Virus 40: Circular SV40 DNA molecules containing lambda phage genes and the galactose operon of Escherichia coli. Proc. Natl. Acad. Sci. USA. 1972;69:2904–2909. doi: 10.1073/pnas.69.10.2904.

[2] Zabner, Joseph et al. 1993 Adenovirus-mediated gene transfer transiently corrects the chloride transport defect in nasal epithelia of patients with cystic fibrosis Cell, Volume 75, Issue 2, 207 – 216.

[3] Using directed attenuation to enhance vaccine immunity, Rustom Antia, Hasan Ahmed, James J Bull, bioRxiv 2020.03.22.002188; doi: https://doi.org/10.1101/2020.03.22.002188

[4] https://www.who.int/vaccine_safety/committee/topics/ebola/Jul_2019/en/

[5] https://www.ema.europa.eu/en/news/first-vaccine-protect-against-ebola

[6] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(16)32621-6/fulltext#seccestitle160

[8] https://www.ema.europa.eu/en/documents/product-information/covid-19-vaccine-astrazeneca-product-information-approved-chmp-29-january-2021-pending-endorsement_en.pdf

[9] https://jvi.asm.org/content/jvi/77/16/8801.full.pdf

[10] https://www.cdc.gov/vaccines/covid-19/hcp/viral-vector-vaccine-basics.html

[11] https://clinicaltrials.gov/ct2/show/NCT04516746

[12] https://www.medrxiv.org/content/10.1101/2021.03.01.21252652v1

[13] https://www.ed.ac.uk/files/atoms/files/scotland_firstvaccinedata_preprint.pdf

[14] https://www.rki.de/DE/Content/Kommissionen/STIKO/Empfehlungen/AstraZeneca-Impfstoff.html

[15] https://www.gov.uk/government/publications/regulatory-approval-of-pfizer-biontech-vaccine-for-covid-19/information-for-uk-recipients-on-pfizerbiontech-covid-19-vaccine#side-effects

[15.1] https://www.astrazeneca.com/media-centre/press-releases/2021/update-on-the-safety-of-covid-19-vaccine-astrazeneca.html

[16] https://www.astrazeneca.at/content/dam/az-at/pdf/2021/Vaccine%20guide%20for%20HCPs%20-%202021-02-02.pdf

[17] Draper, S., Heeney, J. Viruses as vaccine vectors for infectious diseases and cancer. Nat Rev Microbiol 8, 62–73 (2010). https://doi.org/10.1038/nrmicro2240

[18] https://www.frontiersin.org/articles/10.3389/fimmu.2018.01963/full 

[19] https://papers.ssrn.com/sol3/papers.cfm?abstract_id=3777268

[20] https://www.astrazeneca.com/media-centre/press-releases/2020/azd1222hlr.html

[21] https://www.thelancet.com/journals/lancet/article/PIIS0140-6736(20)32661-1/fulltext

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